Tissue residential macrophages (M?) are the first line of defense and one of the key cellular compartments of the innate immune system with specialized sensory, homeostatic, and effector functions that enable host protection from invading pathogens and mount adequate response to tissue damage or stress. If homeostatic signaling pathways in M? become dis-regulated, tissue M? may contribute to pathology and it is currently believed that the vast majority of human acute and chronic diseases develop with significant contributions from pro-pathogenic factors derived from the M? compartment. Through analyzing transcriptional responses and necrotic cell death in vivo, we have made an original observation that despite the efficient trapping of viral and bacterial pathogens from the blood, resident M?s in liver and spleen utilize distinct molecular machineries to execute necrosis and activate pro-inflammatory mediators. Furthermore, we serendipitously found that manipulation of ?1 integrin expression on M? in vitro and in vivo drastically alters their anti-pathogen and pro-inflammatory response phenotypes. Because the phenotypic heterogeneity of tissue M?s became evident only recently and now is a topic of intense research in the field, littl to no information is currently available on generalized molecular mechanisms that drive this heterogeneity both at phenotypic and functional levels. The major goals of this grant proposal are to evaluate the concept that integrins serve as sensors of extracellular cues and guide the functional commitment of M?s to tissue microenvironments and to define the molecular mechanism and signaling pathway(s) that enable ?1 integrin dependent functional specialization of M?s that is critical for balanced homeostatic and/or protective host responses to viral and bacterial pathogens. Therefore, in Specific Aim 1, we will define molecular mechanisms and signaling pathways that enable ?1 integrin-dependent modulation of pro-inflammatory M? responses in vitro. In Specific Aim 2, we will define the role of ?1 integrin in guiding functiona specialization of liver and splenic M?s in vivo. In Specific Aim 3, we will define the role of ?1 integrin in guiding tissue commitment phenotypes of embryonically-derived and adult monocyte-derived M?s in vivo. The proposed studies will provide new mechanistic insights into fundamental cellular and molecular biological processes related to pro- inflammatory M? responses in vivo, and will allow for identification of novel potential therapeutic targets to tame unwarranted severe and/or pathologic inflammation.